The overall aim of this proposal is to understand the role of c-Rel, a member of the NF-kappaB family of transcription factors in regulation of the immune response to the opportunistic pathogen, Toxoplasma gondii. Athough the NF-kappaB family members are associated with the regulation of immune function required for innate and adaptive immunity, little is known about their actual role during infection. Patients with primary and acquired immune deficiencies are highly susceptible to T. gondii infection. Resistance to this pathogen is dependent upon the ability of IL-12 to stimulate the production of IFN-gamma. c-Rel is associated with many events leading to the production of IFN-gamma. For example, c-Rel is associated with the production of IL-12 and is involved in the intracellular signaling pathways of many immune molecules such as CD28 and TNF alpha that enhance IFN-gamma production by NK cells and T cells. Furthermore, c-Rel binding sites have been identified in the promoter of the IL-2 gene and c-Rel -/- T cells are deficient in the production of IL-2 and exhibit proliferation defects. Our studies have shown that c-Rel -/- mice have an increased susceptibility to T. gondii associated with increased numbers of parasites and reduced IFN-gamma production. Preliminary studies suggest that there is an early defect in the production of IL-12 at the site of infection. We have also shown in vivo and in vitro, that c-Rel is essential for IL-12 production from macrophages but not dendritic cells. Based on these preliminary studies, we propose to perform experiments which address the role of c-Rel in the production of IL-12 and IFN-gamma. These studies will allow us to further understand the mechanisms responsible for the increased susceptibility of c-Rel -/- mice to T gondii. In addition, IL-12 and IFN-gamma mediate resistance to many intracellular viral, bacterial and parasitic infections. Our studies will allow us to further understand the mechanisms responsible for the production of IFN-gamma, a cytokine that is critical for resistance to many of the opportunistic infections which affect patients with AIDS.